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Leishmania-induced SHP-1 activation in hepatocytes inhibits NO production

Adhikari, Anupam; Martel, Caroline; Marette, André; Descoteaux, Albert et Olivier, Martin . Leishmania-induced SHP-1 activation in hepatocytes inhibits NO production In: 16e symposium annuel de parasitologie moléculaire du Québec, 6-7 juin 2016, Université McGill, Montréal, QC.

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Leishmania donovani is responsible for the development of visceral leishmaniasis (VL) and is fatal if left untreated. Liver is one of the primary organs that get infected during VL. In this one, Kupffer cells are the main Leishmania-phagocytozing cells, although liver main cellular component are hepatocytes. Interestingly, their role in the context of L. donovani induced pathology is still unravelled. In this project we have investigated to which extend L. donovani infection affects human hepatocytes (HepG2) signalling and functions. Leishmania is known to induce macrophage PTP SHP-1 to hi-jack their functions. To investigate whether similar events could happen in hepatocytes, SHP-1 modulation in L. donovani–infected HepG2 has been monitored. Western blot analysis and PTP assay revealed that SHP-1 was rapidly modulated in HepG2 cells upon L. donovani infection. Additionally, we further observed that L. donovani down-regulates the PKC activity in HepG2 cell line. LPS and LPS/IFN-γ stimulation increase NO production in HepG2 cell line by 3- to 5-fold in comparison to control HepG2. To analyze the impact of Leishmania infection on NO production induced by LPS/IFN-γ, we infected HepG2 cells with L. donovani for several hours and thereafter LPS/IFN-γ stimulation was performed. NO and iNOS expression was found to be reduced in L. donovani-infected HepG2. Correlating with reduced LPS/IFN-γ-induced phosphorylation of various MAPKs family member and PTPs induction in HepG2 cells. In addition, we observed that Ptpn6H-KO mice were more prone to rapidly resolve visceral infection compare to Ptpn6f/f mice. Collectively our study indicates that L. donovani attenuates MAP kinase signalling and iNOS expression in HepG2 cells by activating PTP SHP-1. Our In vivo finding further support that hepatocytes under SHP-1 negative regulation could play a crucial role as a modulator of microbicidal events concurring to control VL.

Type de document: Document issu d'une conférence ou d'un atelier
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 01 mai 2018 20:31
Dernière modification: 01 mai 2018 20:31
URI: https://espace.inrs.ca/id/eprint/7076

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